When animals are exposed to different trace metals for prolonged time periods, each metal produces a biological response profile which specifically characterizes exposure to that metal. The objective of these studies is to assess and characterize response profiles based on a thorough understanding of subcellular mechanisms of metal toxicity and specifically to (1) define and correlate ultrastructural and biochemical responses in vivo which characterize exposure to toxic trace elements following prolonged exposure and (2) develop early, specific, and sensitive, biochemical testing procedures that may be used to evaluate human populations exposed to environmentally important trace elements. Specific metals or other toxicants and areas of interest include the biochemical effects of cadmium, pentenoic acid, arsenic, indium and lead on mitochondrial, microsomal and lysosomal structure and function. These studies have shown the central role played by renal lysosomes in mediating the uptake and toxicity of circulating cadmium-thionein to renal proximal tubule cells. Arsenate-induced alteration of hepatic mitochondrial and microsomal protein synthesis/degradation was found to be associated with changes in urea cycle enzyme activities.